Biomedical subjects
Publications and source records attributed to Y Young.
We examine the linear stability of fluid interfaces subjected to a shear flow. Our main object is to generalize previous work to an arbitrary Atwood number, and to allow for surface tension and weak compressibility. The motivation derives from instances in astrophysical systems where mixing across material interfaces driven by shear flows may significantly affect the dynamical evolution of these systems.
BACKGROUND: The growth of managed health care in the United States has been accompanied by controls on access to specialty physician services. We examined the relationship of physician specialty to treatment and outcomes of patients with asthma in managed care plans. METHODS: We conducted a mail survey of adult asthma patients who were enrolled in 12 managed care organizations and had at least 2 contacts for asthma (International Classification of Diseases, Ninth Revision, Clinical Modification code 493.x) during the previous 24 months; we also surveyed their treating physicians. This report concerns 1954 patients and their 1078 corresponding physicians. Treatment indicators included use of corticosteroid inhalers, use of peak flow meters, allergy evaluation, discussion of triggers, and patient self-management knowledge. Outcome measures included canceled activities, hospitalization or emergency department visits, asthma attacks, workdays lost, asthma symptoms, physical and mental health, overall satisfaction with asthma care, and satisfaction with communication with physicians and nurses. RESULTS: Significant differences were noted for patients of specialists and experienced generalists compared with those of generalist physicians. Peak flow meter possession was reported by 41.9% of patients of generalists, 51.7% of patients of experienced generalists, and 53.8% of patients of pulmonologists or allergists. Compared with patients of generalists, outcomes were significantly better for patients of allergists with regard to canceled activities, hospitalizations and emergency department visits for asthma, quality of care ratings, and physical functioning. Patients of pulmonologists were more likely to rate improvement in symptoms as very good or excellent. CONCLUSIONS: In a managed health care setting, physicians' specialty training and self-reported expertise in treating asthma were related to better patient-reported care and outcomes.
There appears to be a preclinical stage of physical disability which precedes onset of task difficulty (disability) in those who develop disability progressively as a result of chronic disease. Such a stage provides a basis for identifying older adults at risk of becoming disabled. This cross-sectional study evaluated whether a preclinical stage of physical function identified by self-report is associated with decrements in objective physical performance measures or increases in disease; that is, whether these measures, in those with preclinical disability, are intermediate between individuals who report no difficulty and no preclinical changes and those who report difficulty. The Women's Health and Aging Study II, an observational study of 436 women 70-80 years of age who were among the two-thirds least disabled living in the community. Participants were sampled from the HCFA Medicare eligibility lists and were determined eligible if they reported no difficulty, or difficulty in only one of four domains of physical function: mobility, upper extremity, IADL and ADL tasks. At the first follow-up (18 months after baseline), participants completed questionnaires on physical functioning for tasks in each of these domains, with possible answer options for each task: they had (1) difficulty (disabled); (2) no difficulty and no modification of task performance (High Function); or (3) no difficulty but reported modification and/or change in frequency of task performance (a self-report measure of preclinical disability predictive of incident difficulty). At the same visit, standardized, objective measures of function and disease were obtained, including measured walk; chair stands; strength: hip flexion, knee extension, ankle dorsiflexion, and grip; balance: function reach, single leg stand, tandem stand; joint exam: hip pain on passive motion and knee pain or tenderness; spirometry; ankle:arm blood pressure ratio; visual function: acuity, contrast sensitivity, stereopsis; and graded treadmill exercise test. Data were analyzed from the first follow-up examination. Physical performance decreased, and disease frequency increased, in association with decreasing self-reported mobility function (in walking one-half mile and climbing 10 steps), across three self-report categories: High Function, Preclinical Disability (Task Modification but No Difficulty) and Disability (Difficulty). These findings pertained for measures of walking speed, balance, strength, and knee and hip osteoarthritis. Self-reported level of function predicted differences in ranges as well as means for walking speed, balance and strength. These findings indicate a physiologic basis for self-reported function, including preclinical disability, specifically that different levels of disease severity, impairments and physical performance are concurrently associated with different categories of self-reported function. They also suggest new avenues for screening and intervention to prevent disability.
OBJECTIVE: To examine the relationship between risk factors associated with first hip fracture ever and its time to first fracture. METHODS: Data were from the Longitudinal Study on Aging. Of the 7,527 participants, 334 sustained a first hip fracture between 1984 and 1991. RESULTS: Results from the Cox proportional hazards model indicate the time to first fracture was inversely related to the number of risk factors involved. The risk factors significantly associated with first fracture were increasing age, female, Caucasian race, history of falls, insufficient exercise, infrequent church attendance (a likely proxy for outside the home activities), hospitalization in the year before the study, and low body mass index. CONCLUSION: As the number of risk factors increases, the estimated time to fracture becomes shorter; thus, the window of opportunity for prevention is smaller. To reduce the incidence of first hip fracture and to prolong the time to first fracture, interventions should focus on modifiable risk factors identified: increasing exercise, increasing outside-the-home activities, and improving or maintaining body mass index.
An increase in hepatitis A virus (HAV) infection was noted among young men in the former Thames regions during 1997. A retrospective case-control study, using a standardised questionnaire at interview, was conducted in the area most affected (London and East Sussex) to investigate the hypothesis that this increase was mainly among homosexual men and to establish the risk factors associated with transmission. Forty-eight cases and 161 controls completed questionnaires. Forty-one cases (85%) described their sexuality as homosexual (p < 0.0001). Cases were more likely than controls to have eaten shellfish (Odds Ratio (OR) 2.4; 95% Confidence Interval (CI) 1.16, 5.04) during the two months before onset of illness. Cases had more sexual partners (p = 0.015), and more casual sexual partners (p = 0.007) than controls. Cases were more likely to have had sex in a gay sauna (OR 3.5; 95% CI 1.53, 8.30), or in a gay club, pub or disco (OR 2.9; 95 CI 1.29, 6.63) than controls. After adjusting for confounding factors, cases were more likely to have eaten shellfish (adjusted [adj] OR 3.0; 95% CI 1.33, 6.59) and to have had sex in a gay sauna (adj OR 3.9; 95% CI 1.42, 10.59). Public health messages need to inform homosexual men about recognised risk factors such as eating shellfish and travel abroad to endemic areas, as well as sexual risks. Homosexual men can benefit from hepatitis A vaccine. We would suggest that in an outbreak situation men who have multiple anonymous partners and have sex in public venues should be targeted as a priority for health education and immunisation.
In May 2000 a new government target of 70% uptake in people aged 65 and over was introduced for influenza immunisation, with a minimum of 60% uptake in 2000-2001. A postal survey of influenza immunisation coverage in over 75 year olds during 1999-2000 was undertaken in our district's general practices. The evidence on interventions which improve coverage was compared to local practice. General Practitioners and their Primary Care Groups/Trust received feedback on their performance, and best practice was shared. The findings were used to inform the immunisation campaign for 2000-01. The survey response rate was 74%. The district coverage was 50%, ranging from 7% to 97% between practices. Practices achieving high coverage rates combined good patient identification with personalised patient invitation and well-organised clinics. The work that went on in the district achieved an overall influenza immunisation coverage of 62% in 2000-01.
The cerebral deposition of amyloid beta-peptide is an early and critical feature of Alzheimer's disease. Amyloid beta-peptide is released from the amyloid precursor protein by the sequential action of two proteases, beta-secretase and gamma-secretase, and these proteases are prime targets for therapeutic intervention. We have recently cloned a novel aspartic protease, BACE, with all the known properties of beta-secretase. Here we demonstrate that BACE is an N-glycosylated integral membrane protein that undergoes constitutive N-terminal processing in the Golgi apparatus. We have used a secreted Fc fusion-form of BACE (BACE-IgG) that contains the entire ectodomain for a detailed analysis of posttranslational modifications. This molecule starts at Glu(46) and contains four N-glycosylation sites (Asn(153), Asn(172), Asn(223), and Asn(354)). The six Cys residues in the ectodomain form three intramolecular disulfide linkages (Cys(216)-Cys(420), Cys(278)-Cys(443), and Cys(330)-Cys(380)). Despite the conservation of the active site residues and the 30-37% amino acid homology with known aspartic proteases, the disulfide motif is fundamentally different from that of other aspartic proteases. This difference may affect the substrate specificity of the enzyme. Taken together, both the presence of a transmembrane domain and the unusual disulfide bond structure lead us to conclude that BACE is an atypical pepsin family member.
The 52-residue alpha/beta chimera of the epidermal growth factor-like domain in neu differentiation factor (NDFealpha/beta) has been synthesized and folded to form a three disulfide bridge (Cys182-Cys196, Cys190-Cys210, Cys212-Cys221) containing peptide. We investigated two general strategies for the formation of the intramolecular disulfide bridges including, the single-step approach, which used fully deprotected and reduced peptide, and a sequential approach that relied on orthogonal cysteine protection in which specific pairs are excluded from the first oxidation step. Because there are 15 possible disulfide bridge arrangements in a peptide with six cysteines, the one-step approach may not always provide the desired disulfide pairing. Here, we compare the single-step approach with a systematic evaluation of the sequential approach. We employed the acetamidomethyl group to protect each pair of cysteines involved in disulfide bridges, i.e. Cys182 to Cys196, Cys190 to Cys210 and Cys212 to Cys221. This reduced the number of possible disulfide patterns from 15 to three in the first folding step. We compared the efficiencies of folding for each protected pair using RP-HPLC, mapped the disulfide connectivity of the predominant product and then formed the final disulfide from the partially folded intermediate via 12 oxidation. Only the peptide having the Cys182-Cys196 pair blocked with acetamidomethyl forms the desired disulfide isomer (Cys190-Cys210/Cys212-Cys221) as a single homogeneous product. By optimizing both approaches, as well as other steps in the synthesis, we can now rapidly provide large-scale syntheses of NDFealpha/beta and other novel EGF-like peptides.
We have assigned the disulfide structure of Md-65 agouti-related protein (Md65-AGRP) using differential reduction and alkylation followed by direct sequencing analysis. The mature human AGRP is a single polypeptide chain of 112 amino acid residues, consisting of an N-terminal acidic region and a unique C-terminal cysteine-rich domain. The C-terminal domain, a 48 amino acid peptide named Md65-AGRP, was expressed in Escherichia coil cells and refolded under different conditions from the mature recombinant protein. The disulfide bonds in the cystine knot structure of Md65-AGRP were partially reduced using tris(2-carboxyethyl) phosphine (TCEP) under acidic conditions, followed by alkylation with N-ethylmaleimide (NEM). The procedure generated several isoforms with varying degrees of NEM alkylation. The multiple forms of Md65-AGRP generated by partial reduction and NEM modification were then completely reduced and carboxymethylated to identify unreactive disulfide bonds. Differentially labeled Md65-AGRP were directly sequenced and analyzed by MALDI mass spectrometry. The results confirmed that Md65-AGRP contained the same disulfide structure as that of Md5-AGRP reported previously [Bures, E. J., Hui, J. O., Young, Y. et al. (1998) Biochemistry 37, 12172-12177].
Patients with musculoskeletal disorders commonly seek treatment outside orthodox medicine (complementary therapy). In patients attending hospital clinics we investigated the prevalence of such behaviour and the reasons for it. Patients attending rheumatology and orthopaedic clinics who agreed to participate were interviewed on the same day by means of a structured questionnaire in three sections: the first section about demographic characteristics; the second about the nature and duration of the complaint, the length of any treatment and whether the patient was satisfied with conventional treatment; and the third about the use of complementary medicine, the types of therapy that had been considered and the reasoning behind these decisions. The data were examined by univariate and bivariate analysis as well as logistic regression multivariate analysis. 166 patients were interviewed (99% response rate) and the predominant diagnosis was rheumatoid arthritis (22.3%). 109 patients (63%) were satisfied with conventional medical treatment; 63 (38%) had considered the use of complementary therapies, and 47 (28%) had tried such a therapy. 26 of the 47 who had used complementary therapy said they had gained some benefit. Acupuncture, homoeopathy, osteopathy and herbal medicine were the most popular types of treatment to be considered. Patients of female gender (P = 0.009) and patients who had expressed dissatisfaction with current therapies (P = 0.01) were most likely to have considered complementary medicine. These results indicate substantial use of complementary therapy in patients attending musculoskeletal disease clinics. The reasons for dissatisfaction with orthodox treatment deserve further investigation, as does the effectiveness of complementary treatments, which must be demonstrated before they are integrated with orthodox medical practice.
The leptin receptor (OB-R) is a member of the class I cytokine receptor family and mediates the weight regulatory effects of its ligand through interaction with cytoplasmic kinases. The extracellular domain of this receptor is comprised of two immunoglobulin-like and cytokine-receptor homology domains each and type III fibronectin domains. The extracellular domain of human leptin receptor was expressed in and purified from Chinese hamster ovary cells and was found to contain extensive N-glycosylation (approximately 36% of the total protein). The purified protein had a molecular weight of approximately 145,000 and exhibited ligand binding ability as evidenced by formation of ligand-receptor complex, followed by chemical cross-linking. The determined disulfide motif of the soluble leptin receptor contained several distinct cystine knots as well as 10 free cysteines. The N-glycosylation analysis revealed that Asn624 of the WSXWS motif (residues 622-626) within the C-terminal cytokine receptor homology domain was glycosylated, indicating that this region is solvent-exposed. On the other hand, the N-terminal WSXWS motif was not glycosylated.
The agouti-related protein gene (Agrp) plays an important role in body weight regulation. The mature human protein is a single polypeptide chain of 112 amino acid residues, consisting of an N-terminal acidic region and a unique C-terminal cysteine-rich domain. The disulfide structure of recombinant human AGRP was determined by chemical methods using partial reduction with tris(2-carboxyethyl)phosphine under acidic conditions, followed by direct alkylation with N-ethylmaleimide or fluorescein-5-maleimide. Partial reduction and alkylation provided several forms of AGRP that were modified in a stepwise fashion. The resulting proteins were characterized by peptide mapping, sequence analysis, and mass spectrometry, showing that AGRP contained a highly reducible disulfide bond, C85-C109, followed by less reactive ones, C90-C97, C74-C88, C67-C82, and C81-C99, respectively. The chemically defined disulfide connectivity of the recombinant human AGRP was homologous to that of omega-agatoxin IVB except for an additional disulfide bond, C85-C109.
A prospective outcome study was performed on 270 patients, 65 years of age and older, who sustained a femoral neck fracture and underwent hemiarthroplasty. The treatment compared was the use of a noncemented unipolar versus either a cemented or a press fit bipolar prosthesis. The outcome variables assessed included the occurrence of a postoperative complication, length and cost of hospitalization, and function in various quality of life measurements. Patients who underwent bipolar hemiarthroplasty with either a cemented or a press fit prosthesis had better pain relief and function than patients who had a noncemented unipolar prosthesis at a minimum of 24 months after surgery. However, the mean hospitalization cost for patients who had a bipolar prosthesis was $12,290 compared with $8876 for a unipolar prosthesis.
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This study was designed to test the hypothesis that propofol, which possesses antioxidant properties, would produce greater protection than isoflurane in cerebral ischaemia reperfusion injury, at dose levels that produced similar affects on brain electrical activity. Twenty Sprague-Dawley rats were anaesthetized using isoflurane 1.5% in air/oxygen, and mechanically ventilated to a PaCO2 of 4.5 kPa. Following 90 min of middle cerebral artery occlusion using an intraluminal filament, rats were given, in random order, either propofol 1 mg kg-1 min-1 or isoflurane 3% (both of which have been shown to reliably produce EEG burst suppression). After a further 30 min, reperfusion was induced by withdrawing the filament. Animals were killed following 240 min of reperfusion. Rats in the propofol group showed a 21% reduction in mean hemispheric infarct volume when compared with the isoflurane group (P < 0.0001). These data suggest that propofol may act by mechanisms in addition to CMRO2 depression, and provide a basis for further studies of propofol neuroprotection.
The peri-operative management of the only surviving case, to date, of living-related small bowel transplantation is described. The anaesthetic technique was chosen to optimize hepato-splanchnic blood flow. Peri-operative splanchnic blood flow was measured and alterations in flow with changes in inotropic agents and volume loading monitored. There appears to be a role for the use of dopexamine and aggressive volume loading.
Isoflurane has been considered the agent of choice where preservation of splanchnic blood flow is required. Liver blood flow and the hepatic artery buffer response are maintained better in the presence of isoflurane than with other volatile anaesthetic agents. The effects of desflurane have not been assessed in humans. Therefore, we have compared the effects of isoflurane and desflurane anaesthesia on small bowel and hepatic microcirculatory flow during major surgery using laser Doppler flowmetry in a prospective, randomized, single-blind, crossover study. Patients were allocated randomly to receive desflurane or isoflurane (1 MAC) in oxygen-enriched air. Steady-state jejunal and liver blood flow in segment III were assessed by laser Doppler flowmetry. Volatile anaesthetics were then interchanged, and measurements repeated at steady state. Desflurane anaesthesia at 1 MAC was associated with significantly greater gut blood flow than 1 MAC of isoflurane. These differences could not be explained by systemic haemodynamic differences. The similarity in total hepatic flow between groups implies an intact hepatic artery buffer response with desflurane and isoflurane.